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K1-Introduction to

Cancer Biologyby: Dr. Suyatno SpB(K)Onk

BERTHA NAPITUPULU

080100151

FK USU

A2



PERSPECTIVE

Cancer is not modern disease

Hippocrates (± 4oo bc): Cancer as imbalance

between black humor (spleen) and threebodily humor (blood,phlegm, bile)

Sir Percival Pott (1775): one of the first

scientific inquiries in to the cause of the

cancer observed chimney soot as

carcinogen for prostate cancer



Recenly, the most important in knowledgeabout the biology of cancer are

understanding of moleculer genetics

The current model for cancer development cells undergoing a series genetic

mutations and/or alteration, which result

inability to respon normally to intracellular

and/or extracellular signals



Basic molecules of life

All life depends on three critical molecules: DNAs

± Hold information on how cell works RNAs

± Act to transfer short pieces of information todifferent parts of cell

± Provide templates to synthesize into protein Proteins

± Form enzymes that send signals to other cells

and regulate gene activity ± Form bodys major components (e.g. hair, skin,etc.)



Mathematical Biosciences Institute (Ohio State Univ), 2 October 2003

RNA

Protein

DNADOGMA CENTRAL



Central Dogma of Molecular Biology

DNA

RNA

Protein

Transcription

Translation

A gene is expressed in 3 steps:

1) Transcription: RNA synthesis

2) Splicing: removal of intron sequence from RNA

3) Translation: Protein synthesis



Howmuch DNA do we

have?

Humans have 2 x 23 chromosomes EACH cells contains 6 billion bases DNA

That is 1 meter of DNA

A human being has

>100.000.000.000.000 cells That is 100 billion km of DNA



Genetic alteration may arise direct orindirect from:

1. Inherited gen mutations

2. Chemical or radiation induced DNAdamage and genetic instability

3. Incorporation of virus into the cell

4. Random error during DNA synthesis



Characteristic Cancer Growth

Disturbed Growth Control :

- Lose of ³contact inhibition´,

- Need of growth factor is decreased,

- Anchorage independent

Fail of maturationImmortal

Could to transplantation



Cancer:

General

Etiologyand

Pathogen

esis



Carcinogenesis is multi stage process:

± inisiation

± promotion

± progression (malignant tranformation).

Inisiation and promotion cause

acumulation DNA mutation reversibel

eg. displasia

PROGRESSION irreversibel



Step 1: Initiation

Inisiation is exposed cell

by single carcinogenic

agent (inisiator)

Simple mutation in one

or more cellular genes

that control key

regulatory pathways of

the cell

From: Brooks, Chap. 7



Step 2: Promotion

From: Brooks, Chap. 7



Step 3: Progression

Karyotypicinstability

± Increased growthrates

± Increasedinvasiveness

± Increasedhormonalreponsse

± Anaplasia



Interaction Inisiator and Promotor



The Future of Oncology

Since increase understanding of cancer moleculer,

several therapy developed with better outcome

Eg ; patient with chronic myelogenous leukemia can

be treated with succesfully using imatinib (specificcompetitive inhibitor)

In the future, treatment strategies decide on

genetic footprint of the cancer rather than on

histopathological type.



Key words

Oncogenesis: Pathogenesis of neoplasm (b/m)

Carcinogenesis: Pathogenesis of cancer (m)

Carcinogen - agent causing cancer.

Oncogen - agent causing neoplasm.

Mutagen - agent causing mutation.

Tumour Suppressor genes: are genes that act

to inhibit cell proliferation and tumourdevelopment.



Impact on Technical

Operation of Breast Cancer

Ancient CRM/MRM BCT NSP+TRAM



K2-Cancer EpidemiologyHematology Oncology Division

Child Health Departement ² Universtyof Sumatera Utara

20Basic science of Oncology 2011

BERTHA NAPITUPULU

080100151

FK USU

A2



Epidemiology

The study of distribution and determinants of

disease inh

uman population ; wh

ydifferent population or group are at

different risks for diferrent disease

Patterns of incidence and death rates of

malignant disease :

sex,age,race,geography




Childhood cancer

is rare less than 1 % of all cancer inindustrialized countries

Several types of cancer are virtually unique

to childhood, whereas the carcinomas mostfrequently seen in adults

Some of the most striking progress incancer treatment has been made in

paediatric oncology Investigation of childhood tumours has ledto major advances in the understanding of the genetic




Concept epidemiology

1.Disease is not randomlydistributed

2.Disease causation is multifactorial




The scope of Epidemiology

Concerned with population health

Concern to clinicians

Clinical researchers Laboratory scientiest




General approach

What

Who

Where

When

Descriptive epidemiology

Analytic epidemiology Why

How




Types of epidemilogical

Occupational e pidemiology :

effects of workplace exposures on workers

Clini c al e pidemiology : outcome the patients

Geneti c e pidemiology : focus on familes or high

risk individual, concerned with determinants of

disease in families and on inherited causes of

cancer in population Nutritional or environmental epidemiology

Molecular epidemiology




Application epidemiology

Planning

Evaluation of cancer control

Primary prevention Early detection

Scope of cancer epidemiology: broad

concern causes of cancer identificationof population where risk reduced

³prevention´




Cancer statistic

When a patient is diagnosed with cancer

one of the first questions an oncologist will

be asked: ³ how long do I have ³

Survival based statisti c s : observational

st udies : 1.relative 5-year survival rates

2.Overall survival

3.Median survival




Cancer trends

- Relatifve 5-year survival rate for allcancer: 1975 - 1977 : 51%

- 1996 - 2002 : 66%

The reason: Multifactorial:

Increasing:1. diagnostic

test:mammogram,Pap smears,prostate

specific antigen

2.immunosupression

3.the aging of population29Basic science of Oncology 2011



Leading cancer types in Indonesia

1.Cervix cancer

2.Breast cancer

3.Colorectal cancer 4.Lung cancer

5.Nasopharyng cancer

( POI=Perhimpunan Onkologi Indonesia)




Leading cancer types among African

American

Male Prostate

Lung and bronchus

Colon and rectum NHL

Oral cavity

Kidney

Urinary bladder

Pancreas

Stomach

liver

Female Breast

Lung and bronchus

Colon and rectum Uterine corpus

Pancreas

Ovary

NHL

Kidney

Multiple Myeloma

31

Basic science of Oncology 2011



Leading cancer in children

± Leukemia

± Lymphoma and Reticuloendothelial

neoplasms

± CNS tumours

± Retinoblastoma

± Renal Tumours

± Hepatic Tumours




«««.cancer in children

± Malignant Bone tumours

± Soft Tissue sarcomas

± Germ Cell, trophoblastic and other gonadal

neoplasms

± Carcinomas and other malignant epithelial

neoplasms

± Other and unspecified malignant neoplasms




Etiology

Chemical carcinogens

Environmental and industrial carcinogens

Drug induced cancers Radiation carcinogenesis

Viral and immunologic mechanisms




Etiology

A.Chemical carcinogens

1.Industrial exposure

2-Naphthylamine

Benzidine

Bis(chloromethyl)ether

Bis(2-chloroethyl)sulfide(mustard gas)

Vinyl chloride

Certain tars,soots,oils

Chromium compounds

Nickel compounds

Asbestos

Benzene

35




Chemicals

pesticides (CNS tumors)

solvents (eg, CNS tumors, leukemia,neuroblastoma, hepatoblastoma)

metals (hepatoblastoma)

petroleum products (eg, Wilms tumor,leukemia, hepatoblastoma)

lead (Wilms tumor)

boron (Wilms tumor)

furnaces (lymp

homa)

chemotherapy (leukemia)




2.Medical exposure

N,N-bis(2-chloroethyl)-2-

naphthylamine

(Chlornaphazin)

Diethylstilbestrol

Inorganic arsenic comp.

Mephalan,cyclophosphamide

Azathioprine,Phenytoin

3.Societal exposure

Cigarette smoke

Betel nut and tobacco

quid

37




2.Radiation carcinogenesis:medical x-rays,atomic

weapon,radon in house

3.Viral and immunologic mechanisms-Epstein-Barr virus

-Hepatitis-B

-HIV4.Environmental: ultraviolet




Environmental Factors

± Ionizing radiation

Data derived from the atomic bomb

exposures at Hiroshima and Nagasaki

Leukemia

± Electromagnetic fields

Published reports have suggested that

electromagnetic fields have some potential

effect on the promotion of leukemia




Cancer¶s 7 warning signals

1.Change in bowel or bladder habits

2.A sore that does not heal

3.Unusual bleeding or discharge

4.Thickening or lump in breast or elsewhere5.Indigestionor difficulty in swallowing

6.Obvious change in wart or mole

7.Nagging cough or hoarseness

If you have a warning signal ,see your doctor




Role of infection

Epstein-Barr virus (EBV)

Underdeveloped country rate infection in

infancy ,h

igh

the age of onset

HD

-EBV is present in 40 ± 60% of cases

-chronic viral infection activation of cellular

oncogenes, loss of tumour suppressor genes and deregulation of several cytin




± Epstein-Barr viru s ( E BV)

African Burkitt lymphoma

Hodgkin lymp

h

oma Nasopharyngeal carcinoma

± HIV-induc ed immunosu ppr ession

CNS lymphoma

Leiomyosarcoma




K2B-CAR

CINOGE

NE

SISHematology-Oncology Division

Child Health Dept.

University of Sumatera Utara

43

BERTHA NAPITUPULU

080100151

FK USU

A2



Normal human cell populate specific

areas of the body:function,grow,divide in

response to signals (i.e,growth factors) die ( checkpoints cell growth death )

Malignancy : cell develop genetic defects

DN A change lose growth pattern

resistent to celullar mechanism , ability to

acoid programmed cell death , leave their usual sitetravel ± blood stream, lymphatic

system grow in new location

44



Principal genes

Oncogenes

Tumor suppressor genes Apoptosis ( programmed cell death )

45



Oncogenes :genes whose normal functioninvolves promoting the growth andreproduction of cells in regulated

When uncontrolled malignanttransformation of cell

Tumor suppressor genes :normal to ³stop´

cell proliferation

p53P53 lost DN A damage not repair mutation malignant transformation

46



Genesis of malignant tumor : multistep

process , involves derangement of multiple

genes normal function of cells

Most malignancy do not have a clear

hereditary genetic basis

47



Genetic cancer syndromes

Familial Retinoblastoma

Li-Fraumeni syndrome

Wilms¶ Tumor Neurofibromatosis Type I

Familial Adenomatous polyposis

Multiple endocrine neoplasia Hereditary nonpolyposis colon cancer

48



Carcinogenesis :multistage process that leads to

uncontrolled clonal cell growth evolution of

normal cells into malignant cells

Stage carcinogenesis:

1.Transformation

2.Growth

3.Local invasion

4.Metastasis

49



Carcinogen: any subtance when exposed

to living tissue potential to lead cancer

1.Radiation : ultraviolet, ionizing

2.Infection agents: virus,bacteria,flatworms

3.Chemical :

-direct acting initiators: vinyl chloride

-indirect initiators (³procarcinogen´ ) :

polycyclic aromatic hydrocarbon

4.Foreign body reaction :asbestos, silica

50



What are intervals between exposure to a

carcinogen and the development of cancer?

from a few years to decade

Epidemiologic studies very complicated

Smoking related cancers : after 15 years of

exposure Asbestos related cancer : 25 ± 40 years

Ionizing radiation related skin cancer and

leukemia : few years Malignancies of connective tissue , and

adenocarcinoma : 15 ± 30 years

51



Exposure in children

Appear more dangerous

Carcinogenic interval : shorter

Increased overall exposure concentration Increased level of replicating cells

52



How can prevent or minimized

carcinogenesis

Minimize exposure to carcinogen

Don¶t smoke

Maintain healthy diet : adequate fiber , antioxidant

Use sunscreen and limit intense sun exposure Childhood Immunization: avoid viral infection

associated with cancer ( Hepatitis B)

Hereditary risk cancer : ³intensive screening´

Treatment pre-cancerous lesion (e.g.excision) Avoid excessive iatrogenic drug (antineoplastic,

estrogen,oral contraceptive,diethylstilbestrol )

53



How can we prevent or minimize

carcinogenesis?

Choose cancer ± free abcestors

Minimize exposure to carcinogens

Don¶t smoke

Maintain a nutritious diet with antioxidant Use sunscreen and limit intense sun exposure

Immunization: avoid viral infection associated with cancer

Intensive screening: for hereditary risk Treatment of pre-cancerous lesions

Avoid excessive iatrogenic drugs andhormones

54

BERTHA NAPITUPULU



K3-4

BLOK ONCOLOGY

Biochemistry Department

Medical Faculty USU

BERTHA NAPITUPULU

080100151

FK USU

A2



TUMOR GENETICS

PROTOONCOGENES

ONCOGENES

TUMORSUPPRESSOR GENES

CARCINOGENESIS:

MOLECULAR MECHANISM OF TUMOR

CELLULAR TRANSFORMATION



TUMOR MECHANISM

HOW TO DETECT A TUMOR

HOW TO DIAGNOSED

HOW TO UNDERSTAND THE MECHANISM

HOW ARE THE MOLECULAR PATHWAY

IN WHAT CONDITION COULD WE TREAT THE TUMOR

WHAT KIND OF TREATMENT



THE NEW TUMOR DRUGS



Proto Oncogen and Oncogen

Oncogen

± Genes that possess the ability to cause cellular

transformation.

± Act in a dominant fashion, either overexpression or

activating mutations.

Cellular transformation.morphologic changes, loss of contact inhibition,

anchorage independent growth, ability to form

tumors when transplanted into nude mice.



Proto-oncogene.

± Potential to become activated into a cancer

causing oncogene.

± Have been found in all multicellular organisms.

± Would be involved : basic essential functions of the cell related to control of cell proliferation and

differentiation.

± In normal cell : expression is tightly controlled.



Protooncogen productsProtooncogen products

Nucleus

FOS

MYC

JUN

Orga

nella

ERB-B1

FMS

SIS

MOS

ABL

FMSSRC

R AS



Cell Cycle



Cell-cycle control system is based on cyclically

activated protein kinases :

-Cdks (cyclin dependent kinases)

-Cyclins (cdk regulator protein), without

cyclins cdk is inactive.



Proto-oncogenes

1.Growth Factors

± Stimulate cells in stationary stage to enter the cell

cycle.

± Occurs in a two stage process :

Stimulation to proceed into G1 provided by

PDGF,EGF,followed by progression factors :IGF to

progress through the cell cycle.

± Action via autocrine and paracrine model.



2.Growth factor receptors

± Link the information from extracellularenvironment (GF) to a number of different

intracellular signaling pathways.

± The most important : transmembrane receptor

tyrosine kinases.



3. Signal transducers.

± Cytoplasmic nonreceptor tyrosine kinases.

± Proteins with enzyme activity such as

phospholipase C, PI3-K

± Adaptor proteins : Grb2 ± SH2 and SH3 domain.

± Three major pathways : PI3-kinase (PI3-K/AKT

pathway, RAS/mitogen-activated protein kinase

(MAPK) pathway, JAK/STAT pathway.



4. Nuclear proto-oncogene and transcriptionfactors.

± Involved in the control of gene expression by their

action on DNA itself

± Final site of action for messages sent from GF.

± Level at which control of growth and proliferation.



G-Protein and Signal transduction



CARCINOGENESIS

MOLECULAR MECHANISM OF TUMOR

CELLULAR TRANSFORMATION



Mechanisms of oncogene activation

1. Structural alteration.

± Point mutations

± Chromosomal translocation

± Truncated form of protein (transition mutation)

2. Amplification

3. Deregulated expression

± Insertional mutagenesis

± Translocation.



Tumor suppressor genes

Play an important role in tumorigenesis.

Involved in the control of abnormal cell

proliferation.

Loss or inactivation : association with the

development of malignancy.



Viral Oncogene

Three major mechanisms by which an

infectious agent can cause cancer

1. Persistent infection chronic inflammation

repeated cycles of cell damage and cellular

proliferation

accumulate genetic mutations initiation

and promotion of cancer .



RB Pathway

ATM

p14ARF

Cell Survival

NFOB Pathway

ATM

Cytokines Free radicals

DNA Damage

ApoptosisDNARepair

Cellcyclearrest

p53 Pathway

Cytokines, e.g., TNF, IL-1, IL-6, IL-8

ATM

Chronic Inflammation

CHRONIC INFLAMMATION AFFECTSMULTIPLE PATHWAYS

MEK/ERK



2.Direct participation of infectious agents in

the transformation of the cell throughactivation of cellular oncogene pathway.

3. Relevant to HIV : infection may result inimmunosuppression and decreased

recognition of infected or transformed cell by

host immune system.



Gene

Primary

transcript

mRNA

mRNA

Protein

TRANSCRIPTION

Degradation

MODIFICATION / PROCESSING

Degradation

Degradation

Ac tive inac tive

degradation

Trans port

TRANSLATION

NUCLEUS

CYTOPLASM

Mechanisms of retroviral



Mechanisms of retroviral

oncogenesis.

1. Slowly transforming viruses.

± Insertional mutagenesis

2. Acutely transforming viruses.

± Oncogene transduction

3. Trans-acting retroviruses.

± Affect expression or function of cellular growth

and differentiation genes.

HTLV1 ( the only human retrovirus known to directly

cause cancer).



1760-CH

FREE RADICALS AND INFLAMMATION

ROSOH O2-

(Hydroxyl (Superoxide)

radical)

RNSNO ONOO- N2O3

(Nitric Oxide) (Peroxynitrite)

MDA(malondialdehyde)

4HNE(4-hydroxynonenal)

DNA Damageand Mutation

Nitrosamines/Deamination8--oxo-dG

8-nitroguanineEtheno AdductsM1G AdductS-nitrosothiolSSB·sDSB·s

LipidPeroxidation

Arachidonic Acid

Cascade

Eicosanoids

Cell

Proliferation

Protein Damage

(DNARepair Enzymes, Caspases)



Apoptosis

Programmed cell death

Intracellular machinery responsible for

apoptosis is called caspases.

Caspases

Synthesized in the cell as inactive precursor

called procaspases

Usually activated by cleavage at aspartic acidsby other caspases.

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